Genetic and Non-Genetic Modulators of Morbidity/Disability Compression in a Large Population-Based Study of Cognitive and Physical Impairment with Emphasis on Alzheimer's Disease and Related Dementias

在一项基于大规模人群的认知和身体损伤研究中，发病率/残疾压缩的遗传和非遗传调节剂，重点是阿尔茨海默氏病和相关痴呆症

• 批准号: 9913288
• 负责人: P.J. ERIC STALLARD
• 金额: $ 79.99万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9913288
• 关键词: Activities of Daily Living; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Arthritis; Blood; Blood Vessels; Blood specimen; Chronic Disease; Cognitive; Computer software; Constitutional; Coupled; DNA; DNA Methylation; Data; Diabetes Mellitus; Elderly; Epigenetic Process; FOXO3A gene; FRAP1 gene; Family Study; Fracture; Frontotemporal Dementia; Genes; Genetic; Genetic Databases; Genetic Polymorphism; Genotype; Gerontology; Health; Health Care Costs; Health Insurance Portability and Accountability Act; Health and Retirement Study; Heart Diseases; Heterozygote; Hybrid Vigor; Hypertension; IGF1 gene; Impaired cognition; Impairment; Incidence; Individual Differences; Insulin; Lewy Bodies; Life; Life Expectancy; Link; Long-Term Care; Longevity; Malignant Neoplasms; Measures; Mental Depression; Methylation; Morbidity - disease rate; Nucleotides; Obesity; Outcome Measure; Pathway interactions; Phenotype; Population; Population Study; Prevalence; Protocols documentation; Public Health; Reporting; Research; Resolution; Respondent; Risk; Risk Factors; Role; SNP array; SOD2 gene; Sampling; Signal Transduction; Signs and Symptoms; Site; Smoking; Stroke; Surveys; TP53 gene; Testing; Triage; Uncertainty; United States; Variant; Whole Blood; bead chip; biodemography; comorbidity; data cleaning; density; design; disability; end of life; genetic analysis; genetic association; health data; indexing; insight; instrumental activity of daily living; middle age; modifiable risk; mortality; non-genetic; physical inactivity; physically handicapped; public health relevance; trend

Project Summary/Abstract Life expectancy at age 65 increased steadily in the United States over the past half-century. There is great uncertainty, however, regarding the extent to which this increase was accompanied by the compression of morbidity/disability due to Alzheimer’s disease (AD), AD-related dementias (ADRD), and stroke—the leading causes of cognitive impairment (CI) among the elderly—or to heart disease, cancer, diabetes, obesity, arthritis, and fractures—the leading causes of non-cognitive disablement in basic activities of daily living (ADL) among the elderly. Given the aging of the U.S. population and the increasing costs of health care and long-term care above age 65, addressing this uncertainty is of profound public health importance. The 1982–1994 National Long Term Care Survey (NLTCS) produced the first reports of major improvements in ADL and instrumental ADL (IADL) disability rates above age 65. While ADL/IADL improvements continued through 2004 in the NLTCS, dramatically larger improvements occurred for severe cognitive impairment—including AD/ADRD—during 1984– 2004. Moreover, multiple reports from the Health and Retirement Study (HRS) indicated that the favorable trends in severe cognitive impairment continued, but at a slower pace, through 2012; similar reports from the National Health and Aging Trends Study (NHATS) provided additional independent evidence of continuing improvement during 2011–2015. We propose to conduct comprehensive analyses of genetic and non-genetic modulators of the compression of morbidity/disability in the NLTCS, HRS, NHATS, and Long Life Family Study (LLFS), using morbidity/disability criteria consistent with the HIPAA ADL and CI triggers, to test two major hypotheses: (1) that modifiable non-genetic risk factors account for the recent temporal changes in the incidence, prevalence, and continuance of cognitive and physical impairments; and (2) that constitutional genetic and epigenetic factors modulate individual differences in lifetime morbidity/disability incidence, prevalence, and continuance of cognitive and physical impairments. We will analyze the roles of modifiable non-genetic risk factors in longevity, co-morbidity, functional health (ADL/IADL), and severe cognitive impairment (Aim 1). We will complete the SNP array analysis of 2,680 biospecimen samples (918 currently done) and conduct DNA methylation analysis of 639 blood samples in the NLTCS. De-identified NLTCS genetic and epigenetic data will be released using NIAGADS protocols. We will use SNP and DNA methylation data to conduct genetic and epigenetic association analyses with phenotypes of aging, health, longevity, physical disability, and severe cognitive impairment (Aim 2). We will analyze associations of phenotypes of long healthy life with candidate polymorphisms within two highly relevant coupled gene networks—Insulin/IGF1 signaling (incl. FOXO3A and IGFR) and mTOR pathways—linked to aging and longevity across different species and associations of global and pathway-specific indices of heterozygosity with exceptionally high/low morbidity/disability risks; we will determine the roles of AD/ADRD, heart disease, cancer, stroke, and diabetes in these associations (Aim 3).

项目总结/文摘